Oxocarbenium ions are important reactive intermediates in both bioorganic and synthetic organic chemistry. The goal of our research is to deepen our understanding of how steric and electronic effects govern the selective reactions of oxocarbenium and iminium ions and to use these effects to accomplish stereoselective transformations. During the proposed funding period, we will accomplish the following goals: (1) We will demonstrate that the powerful electronic effect exerted by heteroatom substituents on six-membered ring oxocarbenium and iminium ions will control the stereochemical outcomes of both intermolecular and intramolecular nucleophilic attack. (2) We will also show that a variety of heteroatom substituents can be used to control stereoselectivity in these reactions, and we will explore how several substituents interact to reinforce or oppose each other. These experiments will deepen our understanding of electronic influences on stereoselectivity as well as introduce new methods for forming various heteroatom-substituted oxygen and nitrogen heterocycles. (3) We will demonstrate that reactions of medium-ring oxocarbenium and iminium ions will also be controlled by the electronic nature of substituents, therefore leading to new approaches for remote asymmetric induction. (4) With a detailed knowledge of electronic effects on reactions of carbocations, we will demonstrate that this phenomenon can be used as a guiding principle for retrosynthetic analysis. We will complete syntheses of the alkaloid vincarodine, which has been shown to reverse multi-drug resistance in leukemia cells, and laurefucin, a marine natural product with a substitution pattern that will be a demonstration of the powerful influences of electronic effects on oxocarbenium ion conformation.